Rodent obesity is generally associated with hyperleptinemia and leptin resistance. However it is not clear whether the observed leptin resistance is the cause of obesity, or secondary to the increased leptin levels. (In theory, hormone resistance can be either the result or the cause of increased hormone levels). This application proposes to make use of a novel transgenic mouse line to establish the relationship between leptin resistance and hyperleptinemia. These transgenic mice, known as ob/ob TG/+, express leptin constitutively at a low level leading to the development of an obese euleptinemic form. By crossing these mice to different types of leptin resistant mice, it will be possible to establish whether resistance to exogenous leptin is evident in the absence of hyperleptinemia. Experiments will be performed to test whether leptin resistant animals, such as Ay mice, are still resistant to exogenous leptin when endogenous leptin levels are not elevated (as will be the case after crossing to the ob/ob TG/+ mice). The role of specific gene products in the development of leptin resistance will also be tested by mating the ob/ob TG/+ mice to mice with induced mutations in the NPY gene, the MC-4 receptor gene and others. Finally, subtractive cloning using hypothalami from the novel animal models of rodent obesity and controls will be performed. This will permit the identification of additional genes that play a role in the development of obesity and leptin resistance. Thus this application proposes experiments to: (A) Establish the role of hyperleptinemia in the development of leptin resistance in genetically and diet induced obese mice. (B). Explore the possible role of NPY and the MC-4 Receptor (and others) in the development of leptin resistance. (C). Identify novel factors involved in the development of leptin resistance using subtractive cloning.